Systemic antifungals have been used in the treatment of fungal infections since the introduction of griseofulvin in 1958. Since then, new antifungal medications have been introduced, broadening the spectrum of therapies available. Onychomycosis is one of the most common complaints presented to the dermatologist. Fungal infection of the nails, though usually not an urgent medical condition, can be extremely distressing to the patient. Since current topical antifungal medications have little or no efficacy in the treatment of fungal infections of the nail, it is incumbent upon the dermatologist to be familiar with the use of systemic antifungals in the treatment of onychomycosis. In this article, the treatment of fungal infections of the nail with systemic antifungals is discussed. A brief review of the most common types of nail fungal infection is presented and the use of systemic antifungals relevant to dermatology is addressed.